A number of neurological or neuropsychiatric disorders, such as Parkinson's disease, are regarded as being associated with altered amine function in the brain. These amines include dopamine, noradrenalin and serotonin. More particularly, a number of neurological or neuropsychiatric disorders, and especially Parkinson's disease, are associated with the altered dopamine function of neurones found in the nigro-striatal dopamine system and meso-cortical system.
The cell bodies of the neurones comprising the nigro-striatal dopamine system are located in the midbrain and comprise the substantia nigra. The axons of these neurones run in an anterior direction from the midbrain, through the lateral hypothalamus and into the forebrain, terminating in the nucleus caudatus, the globus pallidus and the putamen nucleus.
The cell bodies of the neurones comprising the meso-cortical system are located in the midbrain. The axons of these neurones run in an anterior direction from the midbrain, through the lateral hypothalamus and into the forebrain terminating in structures such as the frontal cortex, the amygdala and other frontal areas. It is thought that hallucinations, cognitive impairment and emotional changes, all of which characterises schizophrenia, are mediated by the production of excess amounts of dopamine in the meso-cortical system.
When the dopamine neurones of the nigro-striatal dopamine system undergo degeneration there is a decrease in normal synaptic transmission. The decrease in synaptic transmission is associated with a depletion of functional dopamine, which in turn decreases the communication between nigro-striatal dopamine system neurones and adjacent neurones. This is an insidious process and takes many years to occur.
In the case of Parkinson's disease, the degeneration of the dopamine neurones also leads to the gradual development of the primary symptoms of Parkinson's disease. These primary symptoms include bradykinaesia or slowness, muscular rigidity and tremor. Secondary symptoms also develop, including depression, anxiety, nocturnal movement or nocturnal myoclonus, akathesia, loss of balance, reduced arm swing, masked face, falling, seborrhea, bradylogia, impaired speech, excessive salivation, freezing, memory loss, bradyphrenia, irritability, mood swing, confusion, disorientation, loss of appetite and insomnia and sometimes excessive sleep.
The degeneration of dopamine neurones in the nigro-striatal dopamine system is believed to be causal to a number of neurological and neuropsychiatric disorders, including Parkinson's disease.
To date, therapies for such neurological and neuropsychiatric disorders are largely aimed at replacing dopamine in the nigro-striatal dopamine system.
The approach adopted to treat Parkinson's disease, and other neurological and/or neuropsychiatric disorders, has been to focus on dopamine replacement, as well as protection and repair of nigro-striatal dopamine neurones by administering dopamine precursors, dopamine agonists, catabolic enzyme inhibitors, antioxidants, foetal cells, stem cells or genetic manipulation to reinstate dopamine function of the nigro-striatal dopamine system.
Some symptomatic relief is usually experienced by the administration of drugs which increase dopamine levels in the nigro-striatal dopamine system. Such drugs include dopamine precursors such as L-dopa, dopamine agonists such as pergolide, bromocriptine or other ergot derivatives, dopamine degradative enzyme inhibitors such as COMT inhibitors or MAO inhibitors such as Comtan® or Deprenyl®. While motor impairment and other symptoms improve with treatment, with time the efficacy of these drugs decrease. When this occurs it is necessary to increase the dose of the drugs that increase dopamine to a point at which side effects become so severe that dyskinaesia and psychosis occur.
It is also possible to implant cells, including foetal or stem cells, into the substantia nigra which grow to function normally and increase dopamine levels. Cell implantation of foetal, neonatal, stem or nigro-striatal dopamine cells for the purpose of increasing dopamine levels is highly invasive and costly. Cell implantation also appears to show limited efficacy.
With the long term use of dopamine replacement, the patient develops excessive involuntary movement and begins to hallucinate, similar to the psychosis seen in schizophrenia. To counteract these side effects a second drug has to be administered, which are typically the same as those prescribed for schizophrenia. Haloperidol, spiroperidol or the atypical neuroleptics are examples of drugs that can be used to treat the psychosis produced by overdoses of dopamine replacement. Similarly, the increased use of recreational drugs, such as heroin, cannabis, ketamine, benzodiazepines and amphetamines also produce a feeling of euphoria and a “psychosis-like’ state that is believed to be mediated by various brain systems including the meso-cortical system and the nigro-striatal dopamine system. To counteract the effects of these drugs the oral administration of various antipsychotic drugs is employed as treatment.
Huntington's Chorea is another disease which is genetically based and is characterised by atrophy of the corpus striatum and increased production of dopamine. The features of this disease include the expression of choriaform movements and hallucination much like those seen with dyskinaesia after dopamine replacement or like those seen in schizophrenia. To treat this disease dopamine receptor blockers and other antipsychotics are often administered systemically (orally) to treat the symptoms.
There is therefore a need to provide improved treatments for neurodegenerative and neuropsychiatric disorders associated with altered amine function.
The retina, situated at the back of the eye, contains numerous cells including, but not limited to, ganglion cells, rods, cones, Type W cells, amacrine cells and dopamine and melatonin-containing cells. One aspect of the “downstream” extension of these cells runs into the optic tract and the thalamus, through structures including the corpus quadrigemini and then onto the visual cortex. It is this pathway which is deemed responsible for processing photic information and is the system that underlies the human ability to experience sight and to possess the sense of visual perception.
A second “downstream” aspect of the extension of these retinal cells runs via the accessory optic tract, through the hypothalamus and into the midbrain where it terminates in several anatomical structures including the dorsal, medial and lateral terminal nuclei of the diencephalon.
A third “downstream” aspect of the extension of these retinal cells runs via the retinal hypothalamic tract, through the suprachiasmatic and paraventricular nuclei of the hypothalamic and other hypothalamic nuclei, through the lateral and posterior-lateral hypothalamus and medial forebrain bundle, through the midbrain, through the spinal column at the level of T1 to T3, through the superior cervical ganglia and the nerve conarii, terminating in pinealocytes of the pineal gland.
It is by the second and, in particular, the third aspect, that the mammalian organism receives diurnal/nocturnal signals from the environment. In the presence of bright light, cells of the retina are stimulated and a signal is sent along the retinal hypothalamic tract to the pineal gland, where the secretion of melatonin is regulated by this stimulus, and melatonin secretion is decreased. In the absence of light stimulation of the retina and the retinal hypothalamic tract, there is a decrease in the inhibitory signal to the pineal gland and with this the secretion of melatonin increases.
Neuroscientific studies and clinical findings that examine the role of melatonin in the occurrence of neuropsychiatric disease suggest that melatonin from the pineal gland is important in its capacity as an antioxidant. In addition, it has been reported that melatonin has an important antioxidative role in the human body and that melatonin deficiency increases with advancing age.